Vinorelbine in the Treatment of Non-Small Cell Lung Cancer

Gridelli, Cesare; Vivo, Rocco De

doi:10.2174/0929867024606777

Cited by 18 publications

(4 citation statements)

References 66 publications

(92 reference statements)

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“…Although vinorelbine, like other vinca alkaloids, induces apoptosis of tumor cells [23] or arrests the cell cycle in G2/M phase [21] by inhibiting the assemblage of tubulin [24], vinorelbine has milder side effects compared to other vinca alkaloids [25,26]. Vinorelbine is applied clinically either alone or in combination with other drugs to treat breast cancer [24] and non-small cell lung cancer [27,28]. In this study, we analyzed signal transduction for vinorelbineinduced apoptosis in human T cell lymphoma, and found that Bid is cleaved by caspases-3 and -9 as well as by caspase-8.…”

Section: Introductionmentioning

confidence: 99%

Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis

et al. 2008

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Vinorelbine is a chemotherapeutic vinca alkaloid clinically prescribed for non-small cell lung cancer and breast cancer. Here we studied the mechanism for vinorelbine-induced apoptosis in a human T-cell lymphoma. Although vinorelbine induces DNA fragmentation that is inhibited by specific peptide inhibitors for caspases-9 and -3 in Jurkat cells, caspase-8 deficiency retards vinorelbine-induced apoptosis. Activation of caspase-8 is also observed in vinorelbine-treated cells, and the activity is diminished when the caspase-3 activity is blocked by a specific peptide inhibitor, Ac-DNLC-CHO. Blocking of the Fas receptor with an antagonistic anti-Fas antibody does not affect vinorelbine-induced DNA fragmentation. These results suggest that vinorelbine-induced apoptosis is enhanced by the activation of caspase-8 via caspase-9-mediated activation of caspase-3, but not through a Fas-triggered signal. Western blotting suggests that vinorelbine cleaves caspase-3, -9 and -8 and reduces the amount of mitochondrial cytochrome c. Caspase-8 deficiency suppresses all of these events. A downstream substrate for caspase-8, Bid, is also cleaved in vinorelbine-treated cells, but the Bid truncation is also observed in caspase-8-deficient Jurkat cells. Importantly, recombinant caspases-3 and -9, as well as caspase-8, directly cleaves recombinant Bid in vitro. These results suggest that caspases-3 and -9 participate in Bid truncation, indicating a new mechanism for vinorelbine-induces apoptosis.

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Section: Introductionmentioning

confidence: 99%

Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis

et al. 2008

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“…Vinorelbine (5Ј nor-anhydro-vinblastine) is a clinically approved drug that is frequently used in the treatment of various cancers, including metastatic breast cancer (Weber et al, 1995) and nonsmall-cell lung cancer (Gridelli and De Vivo, 2002). Vinorelbine is better tolerated than many of the other vinca alkaloids, including reduced neurotoxicity (Mathé and Reizenstein, 1985) due to its reduced affinity for axonal microtubules (Binet et al, 1990).…”

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confidence: 99%

Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine

Drummond¹,

Noble²,

Guo³

et al. 2008

J Pharmacol Exp Ther

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Effective liposomal formulations of vinorelbine (5Ј nor-anhydrovinblastine; VRL) have been elusive due to vinorelbine's hydrophobic structure and resulting difficulty in stabilizing the drug inside the nanocarrier. Triethylammonium salts of several polyanionic trapping agents were used initially to prepare minimally pegylated nanoliposomal vinorelbine formulations with a wide range of drug release rates. Sulfate, poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine intraliposomally while in circulation, with varying degrees of effectiveness. The release rate of vinorelbine from the liposomal carrier was affected by both the chemical nature of the trapping agent and the resulting drug-to-lipid ratio, with liposomes prepared using sucrose octasulfate displaying the longest half-life in circulation (9.4 h) and in vivo retention in the nanoparticle (t 1/2 ϭ 27.2 h). Efficacy was considerably improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon carcinoma model when vinorelbine was stably encapsulated in liposomes using triethylammonium sucrose octasulfate. Early difficulties in preparing highly pegylated formulations were later overcome by substituting a neutral distearoylglycerol anchor for the more commonly used anionic distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal vinorelbine displayed high encapsulation efficiency and in vivo drug retention, and it was highly active against human breast and lung tumor xenografts. Acute toxicity of the drug in immunocompetent mice slightly decreased upon encapsulation in liposomes, with a maximum tolerated dose of 17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal vinorelbine. Our results demonstrate that a highly active, stable, and long-circulating liposomal vinorelbine can be prepared and warrants further study in the treatment of cancer.Nanoparticles such as small unilamellar liposomes have been shown to improve the pharmacokinetics and tumor localization of encapsulated drugs, modify the toxicities associated with a particular drug, and ultimately enhance antitumor efficacy compared with the nonencapsulated drug (Drummond et al., 2008). For the success of liposomal drug delivery, the stable encapsulation of an amphipathic drug in the lumen (Mayer et al., 1985;Haran et al., 1993;Webb et al., 1995;Drummond et al., 2008) of liposomes with long-circulating properties (Allen et al., 2006;Drummond et al., 2008) is preferred, resulting in the ability of such liposomes to localize preferentially in solid tumors through the enhanced permeability and retention effect (Matsumura and Maeda, 1986;Drummond et al., 1999). A liposomal drug is in effect a prodrug, inactive until released from the confines of its carrier, rendering it bioavailable and capable of subsequently acting on its molecular target. Therefore, the ability of the carrier to deliver the active chemical agent to the site of disease, and to subsequently release the drug so as to achieve the desired therapeutic outcome, ar...

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“…2 Vinorelbine has been approved as a treatment for various cancers, including metastatic breast cancer and nonsmall cell lung cancer. 3,4 Vinorelbine is better tolerated than other vinca alkaloids because of a lower propensity for axonal microtubules to cause neurotoxicity. 5 Many studies have put effort into maintaining the vinorelbine concentration surrounding tumor cells in order to improve the anticancer activity of vinorelbine.…”

Section: Introductionmentioning

confidence: 99%

Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

Lee¹,

Chang²,

Huang³

et al. 2012

IJN

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Background The combination of a radioisotope with a chemotherapeutic agent in a liposomal carrier (ie, Indium-111-labeled polyethylene glycol pegylated liposomal vinorelbine, [ 111 In-VNB-liposome]) has been reported to show better therapeutic efficiency in tumor growth suppression. Nevertheless, the challenge remains as to whether this therapeutic effect is attributable to the combination of a radioisotope with chemotherapeutics. The goal of this study was to investigate the pharmacokinetics, biodistribution, and correlation of Indium-111 radioactivity and vinorelbine concentration in the 111 In-VNB-liposome. Methods The VNB-liposome and 111 In-VNB-liposome were administered to rats. Blood, liver, and spleen tissue were collected to determine the distribution profile of the 111 In-VNB-liposome. A liquid chromatography tandem mass spectrometry system and gamma counter were used to analyze the concentration of vinorelbine and radioactivity of Indium-111. Results High uptake of the 111 In-VNB-liposome in the liver and spleen demonstrated the properties of a nanosized drug delivery system. Linear regression showed a good correlation ( r = 0.97) between Indium-111 radioactivity and vinorelbine concentration in the plasma of rats administered the 111 In-VNB-liposome. Conclusion A significant positive correlation between the pharmacokinetics and biodistribution of 111 Indium radioactivity and vinorelbine in blood, spleen, and liver was found following administration of the 111 In-VNB-liposome. The liposome efficiently encapsulated both vinorelbine and Indium-111, and showed a similar concentration-radioactivity time profile, indicating the correlation between chemotherapy and radiotherapy could be identical in the liposomal formulation.

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Vinorelbine in the Treatment of Non-Small Cell Lung Cancer

Cited by 18 publications

References 66 publications

Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis

Bid truncation mediated by caspases-3 and -9 in vinorelbine-induced apoptosis

Improved Pharmacokinetics and Efficacy of a Highly Stable Nanoliposomal Vinorelbine

Correlation between radioactivity and chemotherapeutics of the 111In-VNB-liposome in pharmacokinetics and biodistribution in rats

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